The principal investigator, working in collaboration with Dr. Boyd Hartman, discovered that catecholaminergic re-uptake blockers have profound effects on brain permeability. Such drugs increase the cerebral extraction of substances such as water and ethanol which are normally diffusion-limited. This drug effect on the blood:brain barrier is consistent with the hypothesis that one function of central adrenergic neurons is regulation of cerebral permeability and blood flow. The research proposed here will further test this hypothesis by: (a) attempting to abolish the effect by ablating central adrenergic neurons with neurotoxins as well as pharmacologically blocking central adrenergic receptors; (b) studying the ability of other drugs with central catecholaminergic actions to produce similar barrier alterations; and (c) studying the effect of electrical stimulation of central adrenergic neurons on the cerebral extraction of water. A dual label radioisotope technique has been developed to measure the cerebral extraction of diffusion-limited substances. This technique will be further modified during the course of these studies to provide a reliable and inexpensive means of simultaneously measuring both cerebral extraction ad cerebral blood flow.